The present invention is directed to aminobiguanides having antimicrobial activity, and to the use of these aminobiguanides in pharmaceutical compositions. More specifically, the invention is directed to use of the subject aminobiguanides in compositions and methods for disinfecting contact lenses, and to the use of these compounds to preserve various types of pharmaceutical compositions from microbial contamination, particularly ophthalmic and otic pharmaceutical compositions.
Contact lenses are exposed to a broad spectrum of microbes during normal wear and become soiled relatively quickly. Routine cleaning and disinfecting of the lenses are therefore required. Although the frequency of cleaning and disinfecting may vary somewhat among different types of lenses and lens care regimens, daily cleaning and disinfecting is normally required. Failure to clean and disinfect the lens properly can lead to a multitude of problems ranging from mere discomfort when the lenses are being worn to serious ocular infections. Ocular infections caused by particularly virulent microbes, such as Pseudomonas aeruginosa, can lead to loss of the infected eye(s) if left untreated or if allowed to reach an advanced stage before treatment is initiated. It is therefore extremely important that patients disinfect their contact lenses in accordance with the regimen prescribed by their optometrist or ophthalmologist.
Unfortunately, patients frequently fail to follow the prescribed regimens. Many patients find regimens to be difficult to understand and/or complicated, and as a so result do not comply with one or more aspects of the regimen. Other patients may have a negative experience with the regimen, such as ocular discomfort attributable to the disinfecting agent, and as a result do not routinely disinfect their lenses or otherwise stray from the prescribed regimen. In either case, the risk of ocular infections is exacerbated.
Despite the availability of various types of contact lens disinfecting systems, such as heat, hydrogen peroxide, and other chemical agents, there continues to be a need for improved systems which: 1) are simple to use, 2) have potent antimicrobial activity, and 3) are nontoxic (i.e., do not cause ocular irritation as the result of binding to the lens material). There is also a need for chemical disinfecting agents that retain their antimicrobial activity in the presence of salts (e.g., sodium chloride) and other components of compositions utilized to treat contact lenses. For example, U.S. Pat. No. 4,438,011 (Howes) states that ionic species such as chloride inhibit the antimicrobial activity of the biguanide chlorhexidine, and teaches that the concentration of such ionic species must therefore be limited in order to maintain adequate antimicrobial activity for disinfecting contact lenses.
There is also a need for an improved means of preserving pharmaceutical compositions from microbial contamination. This need is particularly prevalent in the fields of ophthalmic and otic compositions. The antimicrobial agents utilized to preserve aqueous ophthalmic and otic compositions must be effective in preventing microbial contamination of the compositions when used at concentrations that are non-toxic to ophthalmic and otic tissues.
The present invention is directed to satisfying the above-cited needs.
The present invention is directed to certain aminobiguanides having antimicrobial activity and to pharmaceutical compositions containing one or more of these aminobiguanides to preserve the compositions from contamination by microorganisms. The invention is also directed to the use of the subject aminobiguanides to disinfect contact lenses.
The aminobiguanides of the present invention have excellent antimicrobial activity, even at very low concentrations. These compounds retain excellent antimicrobial activity, even in the presence of salt-containing media, such as saline solutions. The retention of antimicrobial activity in the presence of sodium chloride and other salts is highly significant, since such salts are commonly found in pharmaceutical compositions. For example, sodium chloride and other salts are frequently used to adjust the osmolality of ophthalmic compositions, so as to make the compositions isotonic with human tears. Sodium chloride or other salts may also be present in aqueous otic compositions. Moreover, compositions utilized to treat contact lenses frequently contain cleaning agents or other ingredients that may also have a negative effect on the activity of antimicrobial agents. The ability of the aminobiguanides of the present invention to retain a high level of antimicrobial activity, even in the presence of salts and other ingredients of pharmaceutical compositions, is therefore an important feature of the present invention.
The aminobiguanide compounds of the present invention have the following formula: 
wherein:
R1, R2, R3 and R4 are the same or different and are selected from hydrogen, alkyl (C1 to C20), aminoalkyl (C1 to C20), aryl, arylalkyl (C3 to C20), aryloxyalkyl (C3 to C20) and cycloalkyl (C3 to C20); and X is alkyl (C2 to C20), optionally containing one or more substituents selected from the group consisting of cycloalkyl (C3 to C20), aryl, arylalkyl (C3 to C20) and aryloxyalkyl (C3 to C20).
In the foregoing definitions of the R1, R2, R3, R4 and X substituents, the alkyl groups may be saturated or unsaturated and may be in the form of either straight or branched chains, and all of the groups other than hydrogen may contain one or more heteroatoms. The compounds of the present invention also include pharmaceutically acceptable salts of the compounds of formula (I).
The preferred compounds of formula (I) are those wherein R1, R2, R3 and R4 are selected from the group consisting of hydrogen, alkyl (C1 to C20), aminoalkyl (C1 to C20) and cycloalkyl (C3 to C20), and X is selected from the group consisting of alkyl (C2 to C20) and alkyl (C2 to C20) substituted with one or more cycloalkyl (C3 to C20) groups.
The most preferred compounds are those wherein R1, R2, R3 and R4 are hydrogen or C1 to C20 alkyl, and X is C2 to C10 alkyl or C2 to C10 alkyl containing one or more cycloalkyl (C3 to C20) substituents. Examples of such compounds are set forth in the following table:
The compound wherein X is propyl, R1 is methyl, R2 is dodecyl, R3 is hydrogen and R4 is 1,4-dimethylpentyl (i.e., Compound Number 1) is the most preferred compound of formula (I).
The compounds of formula (I) may be synthesized in accordance with the following reaction scheme: 
Suitable methods for synthesizing the compounds of formula (I) are further demonstrated by the following examples, which describe the synthesis of certain preferred compounds: